Adenylyl Cyclase Activation Modulates Activity-Dependent Changes in Synaptic Strength and Ca2+/Calmodulin-Dependent Kinase II Autophosphorylation

Activation of the Ca 2+ - and calmodulin-dependent protein kinase II (CaMKII) and its conversion into a persistently activated form by autophosphorylation are thought to be crucial events underlying the induction of long-term potentiation (LTP) by increases in postsynaptic Ca 2+ . Because increases in Ca 2+ can also activate protein phosphatases that oppose persistent CaMKII activation, LTP induction may also require activation of signaling pathways that suppress protein phosphatase activation. Because the adenylyl cyclase (AC)–protein kinase A signaling pathway may provide a mechanism for suppressing protein phosphatase activation, we investigated the effects of AC activators on activity-dependent changes in synaptic strength and on levels of autophosphorylated αCaMKII (Thr 286 ). In the CA1 region of hippocampal slices, briefly elevating extracellular Ca 2+ induced an activity-dependent, transient potentiation of synaptic transmission that could be converted into a persistent potentiation by the addition of phosphatase inhibitors or AC activators. To examine activity-dependent changes in αCaMKII autophosphorylation, we replaced electrical presynaptic fiber stimulation with an increase in extracellular K + to achieve a more global synaptic activation during perfusion of high Ca 2+ solutions. In the presence of the AC activator forskolin or the protein phosphatase inhibitor calyculin A, this treatment induced a LTP-like synaptic potentiation and a persistent increase in autophosphorylated αCaMKII levels. In the absence of forskolin or calyculin A, it had no lasting effect on synaptic strength and induced a persistent decrease in autophosphorylated αCaMKII levels. Our results suggest that AC activation facilitates LTP induction by suppressing protein phosphatases and enabling a persistent increase in the levels of autophosphorylated CaMKII.